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Open Full Page Published OnlineFirst May 4, 2016; DOI: 10.1158/1078-0432.CCR-15-2709 CCR Drug Updates Clinical Cancer Research Talimogene Laherparepvec for the Treatment of Advanced Melanoma Patrick A. Ott1,2 and F. Stephen Hodi1,2 Abstract Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic skin or lymph nodes. The drug is currently in clinical trials as virus that mediates local and systemic antitumor activity by direct monotherapy and in combination with immune-checkpoint inhi- cancer cell lysis and an "in situ vaccine" effect. Based on an increased bitors and radiotherapy in melanoma and other cancers. The durable response rate compared with granulocyte macrophage– mechanism of action, toxicity, and efficacy as well as its role in colony stimulating factor in a randomized phase III trial, it was current clinical practice and potential future applications are approved by the FDA for the treatment of melanoma metastatic to reviewed. Clin Cancer Res; 22(13); 3127–31. Ó2016 AACR. Introduction factor (GM-CSF) in the process. The genes encoding neuroviru- lence infected cell protein 34.5 (ICP34.5) and the infected cell Novel systemic treatment modalities such as inhibition of the protein 47 (ICP47) are functionally deleted in the virus, while the immune checkpoints CTLA-4 and PD-1/PD-L1 as well as BRAF gene for human GM-CSF is inserted. ICP34.5 is required for viral and MEK inhibition have expanded the range of therapeutic replication in normal cells, which is mediated by interaction with modalities for advanced melanoma (1–11). The antitumor activ- proliferating cell nuclear antigen (PCNA; ref. 14), whereas cancer ity of both MAPK pathway–targeted therapy (for BRAFV600- cells proliferate independently of ICP34.5 expression. ICP47 is mutant melanoma) and immune checkpoint inhibition (inde- critical for the evasion of HSV-infected cells from cytotoxic T cells pendent of a BRAF mutation) with response rates of 60% and by interfering with peptide processing and presentation on higher is striking and has improved the prognosis for many MHC-1 (15). Deletion of ICP47 in T-VEC prevents potentially patients. Both CTLA-4 and/or PD-1/PD-L1 blockade with mono- limited viral antigen presentation, which could compromise its clonal antibodies can achieve durable clinical benefit, suggesting function as an in situ vaccine. ICP47 deletion also leads to that endogenous tumor directed T-cell responses, suppressed by increased expression of the US11 gene, resulting in increased inhibitory pathways such as CTLA-4 and/or PD-1/PD-L1, can be virus replication in cancer cells without decreasing tumor selec- invigorated, resulting in effective tumor control (1, 2, 10–13). tivity. GM-CSF is a proinflammatory cytokine that promotes the Many patients experience primary or secondary resistance to PD-1 recruitment and maturation of dendritic cells (DC) as well as and/or CTLA-4 inhibition. Alternative treatments for these macrophages into potent antigen-presenting cells, leading to patients are therefore still urgently needed. Talimogene laherpar- priming of tumor-specific T cells (16). It has been used success- epvec (T-VEC), an agent with a different and potentially comple- fully as an immune adjuvant in many cancer vaccines. mentary mechanism of action to immune checkpoint blockade, is T-VEC has two distinct mechanisms of action: The lytic a recent addition to the therapeutic armamentarium for patients function of the virus destroys tumor cells directly, whereas the with advanced melanoma. lysis of the cancer cells leads to release of tumor antigens, virus, and GM-CSF, attracting DCs, thereby creating an in situ vaccine Mechanism of Action (Fig. 1). In a subcutaneous murine melanoma model, tumor T-VEC is an intralesionally delivered oncolytic immunotherapy growth inhibition on the contralateral, uninjected site was only comprised of a genetically engineered attenuated herpes simplex seen when T-VEC contained GM-CSF, establishing a systemic virus type 1 (HSV-1) of the JS-1 strain. T-VEC invades both effect of the lytic virus that is likely mediated by a host immune cancerous and healthy cells but can only replicate in cancer cells, response (17, 18). where it secretes granulocyte macrophage–colony stimulating Clinical Development Phase I 1Department of Medical Oncology, Melanoma Disease Center, and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard In a phase I study, 30 patients with previously treated mela- Medical School, Boston, Massachusetts. 2Department of Medicine, noma, breast cancer, gastric adenocarcinoma, or head and neck Brigham and Women's Hospital, Boston, Massachusetts. cancer who had cutaneous or subcutaneous lesions accessible Corresponding Author: Patrick A. Ott, Melanoma Disease Center & Center for for injections were treated with different doses and schedules Immuno-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Bos- of T-VEC (19). The most common adverse events were grade 1 ton, MA 02215. Phone: 617-582-9030; Fax: 617-632-6727; E-mail: fever, constitutional symptoms, nausea, anorexia, and injec- [email protected] tion site reactions. One patient was reported to experience doi: 10.1158/1078-0432.CCR-15-2709 grade 2 fever, rigor, hypotension, tachycardia, and constitu- Ó2016 American Association for Cancer Research. tional symptoms. Overall, the toxicities were more intense in www.aacrjournals.org 3127 Downloaded from clincancerres.aacrjournals.org on October 3, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst May 4, 2016; DOI: 10.1158/1078-0432.CCR-15-2709 Ott and Hodi Dendritic cells Figure 1. In situ vaccination effect of T-VEC, potentially converting a non–T-cell- inflamed tumor to a T-cell–inflamed T-VEC Lysed tumor tumor. Replication of T-VEC in tumor cells cells leads to their lysis with release of tumor antigens, viral antigens and pathogen-associated molecular Inflammatory patterns (viral DNA, RNA, and cytokines T cells proteins), and GM-CSF. This process (IFNγ, TNFβ) results in the recruitment and Noninflamed GM-CSF Inflamed maturation of antigen-presenting cells, “cold” tumor “hot” tumor including dendritic cells, which present tumor antigens to cytotoxic CD8 T cells. © 2016 American Association for Cancer Research HSV-seronegative patients; an initial low dose of T-VEC, lead- was administered until CR, clinically significant progressive dis- ing to HSV seroconversion, followed by a series of higher-dose ease, intolerable side effects, or 12 months of therapy without an injections was better tolerated. There were no partial or com- objective response. As in the phase II study, T-VEC was initially plete responses (CR); however, flattening of both injected administered at 106 pfu/mL for seroconversion, whereas subse- and noninjected metastases was seen in 6 of 26 evaluable quent doses were given at 108 pfu/mL 3 weeks after the first dose patients. Posttreatment biopsies of injected lesions showed and then every 2 weeks. T-VEC injection was restricted to cuta- inflammation and necrosis. neous and subcutaneous metastases; different lesions could be prioritized for injection differently at any visit depending on its size and the emergence of new lesions. GM-CSF was given daily Phase II subcutaneously at 125 mg/m2 during the first 14 days of a 28-day Fifty patients with unresectable stage IIIC–IV melanoma with cycle; it was chosen as a comparator arm based on overall survival one or more injection-accessible tumor lesions were enrolled (OS) benefit compared with historical controls observed in a in a phase II study assessing the response rate, survival, and safety previous study in melanoma patients at high risk for recurrence of T-VEC (20). Thirty-seven (74%) of the patients had received (23). The primary endpoint was durable response rate (DRR), prior systemic therapy and 20 (40%) had M1c visceral disease. defined as PR or CR with an onset during the first 12 months of Based on the experience from the phase I study, patients received treatment and lasting for at least 6 months. Secondary endpoints intratumoral injections of up to 4 mL of 106 pfu/mL of T-VEC, included OS, best overall response, and duration of response. followed 3 weeks later by up to 4 mL of 108 pfu/mL, and Approximately half of the patients in each arm were previously subsequently every 2 weeks for a maximum of 24 treatments. In untreated; 45% of patients in the T-VEC arm and 39% of patients a small subset of patients, peripheral blood and tumor biopsies þ þ in the GM-CSF arm were stage IVM1b/c. The study met its primary were obtained for assessment of effector T cells, CD4 FoxP3 þ þ endpoint: DRR was significantly higher in the T-VEC arm (16.3%) regulatory T cells (Treg), CD8 FoxP3 suppressor T cells, and compared with the GM-CSF arm (2.1%). The overall response rate myeloid-derived suppressive cells (MDSC; ref. 21). Eight CRs and was also significantly increased in the T-VEC arm (26.4%) com- five partial responses (PR) were observed, resulting in an overall pared with GM-CSF alone (5.7%) as was the number of CRs response rate (ORR) of 26%. Twelve of the 13 responses lasted (10.8% vs. 1%). The median OS was 23.3 months in the T-VEC longer than 6 months. Compared with untreated melanoma arm and 18.9 months in the GM-CSF arm (HR, 0.79; 95% CI, lesions, melanoma metastases regressing after treatment with 0.62–1.00; P ¼ 0.051), and it was therefore unclear, at least from T-VEC exhibited an increase of MART-1–specific T cells compared the primary study analysis, whether T-VEC was associated with with melanoma lesions from untreated patients, whereas num- improved OS. bers of Tregs and MDSCs were decreased. Evidence for increased Subgroup analyses showed higher antitumor activity of T-VEC MART-1–specific T cells was seen in tumor-infiltrating lympho- in patients with stage IIIB, IIIC, and IVM1a disease: with T-VEC, cytes (TIL) and peripheral blood from a patient with a CR after T- DRR was 33% in patients with IIIB or IIIC and 16% in patients TVEC, suggesting the induction of a systemic melanoma-specific with stage IVM1a, respectively compared with 0% and 2% with immune response.
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